Following the 1987 outbreak of toxicity in Eastern Canada, due to consumption of cultured mussels contaminated with the potent neuroexcitatory amino acid domoic acid (DA), increasing attention has been devoted to the features and mechanisms of DA neurotoxicity. In rodents, non-human primates and in humans, DA causes neuronal death particularly in the hippocampus and the amygdala. Parallel to these neuropathological effects, behavioral changes are also apparent, particularly memory loss. Neurotoxicity of DA is related to activation of a subtype of receptors for the neurotransmitter glutamate, the receptors for kainic acid (KA). Activation of KA receptors leads to calcium overload, and to increased production of free radicals and enhanced lipid peroxidation, which in turn cause disruption of cellular functions and integrity. Age appears to be an important factor in modulating DA neurotoxicity: older animals and pups appear to be more sensitive to DA neurotoxicity than adult animals. The aim of this project is to elucidate molecular and cellular mechanisms of DA-induced developmental neurotoxicity. Special emphasis will be given to the identification of factors that impact age-related susceptibility to DA induced neurotoxicity, with a focus on the role of oxidative stress and on antioxidant defense mechanisms. The latter systems can be affected, in addition to age, by genetic polymorphisms of antioxidant-related enzymes and by dietary factors. Most of the toxicological research on DA has focused on high acute models of toxicity in adults and the elderly. This proposed project will focus on the newly emerging evidence that suggests evaluation of low level chronic DA exposures may be of equal or greater public health importance. The proposed research will emphasize the identification of age and genetic related susceptibility factors. We will utilize both in vitro and in vivo embryonic and postnatal rodent models for our mechanistic studies, taking advantage of newly available transgenic mice with antioxidant pathway changes reflective of human variability in these pathways to evaluate specific defense mechanisms. We will take advantage of newly established genomic and proteomic facilities at the University of Washington to evaluate the dynamics of molecular mechanisms of domoic acid.